Bertron M. Groves

Primary pulmonary hypertension. A national prospective study.

A national registry was begun in 1981 to collect data from 32 centers on patients diagnosed by uniform criteria as having primary pulmonary hypertension. Entered into the registry were 187 patients with a mean age (+/- SD) of 36 +/- 15 years (range, 1 to 81), and a female-to-male ratio of 1.7:1 overall. The mean interval from onset of symptoms to diagnosis was 2 years. The most frequent presenting symptoms included dyspnea (60%), fatigue (19%), and syncope (or near syncope) (13%). Raynaud phenomenon was present in 10% (95% of whom were female) and a positive antinuclear antibody test, in 29% (69% female). Pulmonary function studies showed mild restriction (forced vital capacity [FVC], 82% of predicted) with a reduced diffusing capacity for carbon monoxide (DLCO), and hypoxemia with hypocapnia. The mean (+/- SD) right atrial pressure was 9.7 +/- 6 mm Hg; mean pulmonary artery pressure, 60 +/- 18 mm Hg; cardiac index, 2.3 +/- 0.9 L/min X m2; and pulmonary vascular resistance index, 26 +/- 14 mm Hg/L/min X m2 for the group. Although no deaths or sustained morbid events occurred during the diagnostic evaluation of the patients, the typically long interval from initial symptoms to diagnosis emphasizes the need to develop strategies to make the diagnosis earlier.

Changes in gene expression in the intact human heart. Downregulation of alpha-myosin heavy chain in hypertrophied, failing ventricular myocardium.

Using quantitative RT-PCR in RNA from right ventricular (RV) endomyocardial biopsies from intact nonfailing hearts, and subjects with moderate RV failure from primary pulmonary hypertension (PPH) or idiopathic dilated cardiomyopathy (IDC), we measured expression of genes involved in regulation of contractility or hypertrophy. Gene expression was also assessed in LV (left ventricular) and RV free wall and RV endomyocardium of hearts from end-stage IDC subjects undergoing heart transplantation or from nonfailing donors. In intact failing hearts, downregulation of beta1-receptor mRNA and protein, upregulation of atrial natriuretic peptide mRNA expression, and increased myocyte diameter indicated similar degrees of failure and hypertrophy in the IDC and PPH phenotypes. The only molecular phenotypic difference between PPH and IDC RVs was upregulation of beta2-receptor gene expression in PPH but not IDC. The major new findings were that (a) both nonfailing intact and explanted human ventricular myocardium expressed substantial amounts of alpha-myosin heavy chain mRNA (alpha-MHC, 23-34% of total), and (b) in heart failure alpha-MHC was downregulated (by 67-84%) and beta-MHC gene expression was upregulated. We conclude that at the mRNA level nonfailing human heart expresses substantial alpha-MHC. In myocardial failure this alteration in gene expression of MHC isoforms, if translated into protein expression, would decrease myosin ATPase enzyme velocity and slow speed of contraction.

Antinuclear antibodies in primary pulmonary hypertension

The association of positive antinuclear antibodies with the clinical and hemodynamic features of 43 patients with primary pulmonary hypertension and 16 patients with secondary pulmonary hypertension was investigated. Each patient had determinations of antinuclear antibodies using a KB cell substrate immunofluorescent test. Of the patients with primary pulmonary hypertension, 40% had positive antinuclear antibodies at titers of 1:80 dilutions or greater. There were no differences between patients with primary pulmonary hypertension and positive antinuclear antibodies compared with those with negative antinuclear antibodies in relation to clinical or hemodynamic status. A 6% incidence rate of antinuclear antibodies was found in patients with secondary pulmonary hypertension, similar to that in the normal population. The clinical, hemodynamic, serologic and histologic similarity between patients with primary pulmonary hypertension and those with unexplained pulmonary hypertension associated with collagen vascular disorders suggests that primary pulmonary hypertension in some patients may represent a collagen vascular disease confined to the lungs. The frequency of positive antinuclear antibody tests would place primary pulmonary hypertension between rheumatoid arthritis and scleroderma in the spectrum of collagen vascular diseases. Further studies are necessary, however, before one might expect that immunosuppressive therapy would be beneficial to these patients.

Operation Everest II: Cardiac filling pressures during cycle exercise at sea level☆

To examine the relationship between cardiac filling pressures during exercise in man and oxygen transport, we examined sea level data from Operation Everest II. The results showed that, (1) both right atrial and wedge pressures rose with heavy exercise in normal man, (2) the magnitude of the rise in these filling pressures related both to stroke volume and maximum exercise capacity, (3) wedge pressure was tightly coupled to right atrial pressure, with each mm Hg increase in right atrial pressure resulting in a 1.4 mm Hg increase in wedge pressure, and (4) very high wedge pressures occurred (in some subjects greater than 30 mm Hg), which contributed to an elevation of pulmonary arterial pressure. Thus direct measurements indicate right heart filling pressure increases with exertion in normal man, probably providing the necessary right heart output to fill the left heart. We speculated that the high cardiac filling pressures might be needed to maintain oxygen transport during heavy exercise, and that such pressures could contribute both to elevated pulmonary arterial pressure and to increased filtration of water into the lung.

3D coronary reconstruction from routine single-plane coronary angiograms: clinical validation and quantitative analysis of the right coronary artery in 100 patients.

Background: Current coronary angiographic techniques display complex three-dimensional (3D) coronary structures in two dimensions (2D). We have developed a 3D reconstruction (3DR) algorithm using standard single-plane angiographic images that allows for 3D display of coronary structures. The purpose of this study was to validate our 3DR algorithm and quantify anatomic characteristics of the right coronary artery (RCA) in vivo. Methods: Accuracy and reproducibility studies were performed using 3DRs of a coronary phantom and in vivo following 3DRs in 40 patients. The anatomic features of the RCA were then quantified in 100 patients. Results: Comparison of length and bifurcation angles (BA) from the phantom to the 3DRs revealed good accuracy and correlation for both (r = 0.95 and 0.93 respectively), with diameter error of <7%. In vivo, the average root mean square (RMS) error in the spatial coordinates of the vessel centerlines was 3.12 ± 0.77 and 3.16 ± 0.75 mm in 20 left coronary arteries (LCA) and 20 RCAs respectively. Interobserver average RMS error was 3.47 ± 1.96 mm and intraobserver average RMS error was 3.02 ± 1.07 and 3.44 ± 1.57 mm for two different operators (p = NS). The average RCA length was 10.2 ± 1.7 cm, average radius of curvature (ROC) was 52 ± 9°, and the average 3D bifurcation angle of the posterior descending artery (PDA) from the RCA was 55 ± 22°. Foreshortening (FS) of the segments of the RCA in three standard’ projections ranged from 0–60, 0–75, and 0–82% respectively. Conclusions: Using our 3DR algorithm patient-specific anatomic characteristics can be accurately displayed and quantified, expanding the information that can be derived from routine coronary angiography.

Randomized study of the safety and clinical utility of rotational angiography versus standard angiography in the diagnosis of coronary artery disease.

This study evaluates the safety and clinical utility of rotational angiography in the diagnosis of coronary artery disease. High‐speed rotational angiography is a newly available angiographic modality that gives a dynamic multiple‐angle perspective of the coronary tree during a single contrast injection. We prospectively randomized 56 patients referred for diagnostic coronary angiography to either standard or rotational angiography. Contrast and radiation utilization were compared between the two groups. The number of additional cine acquisitions needed was used to determine adequacy of the diagnostic study protocol. Rotational angiography was successfully completed in all subjects. There was a 33% reduction in contrast utilization in the rotational group as compared to the standard group (35.6 ± 12.6 vs. 52.8 ± 10.7 ml, respectively; P < 0.0001). Additionally, there was a 28% reduction in total radiation exposure in the rotational group as compared to the standard group (39.0 ± 18.5 vs. 53.9 ± 23.4 Gycm2, respectively; P = 0.01). Total whole‐body radiation exposure to the primary operator was 144 mrem with rotational angiography and 170 mrem with standard angiography. Procedure time tended to be shorter for rotational angiography (353.9 ± 146.7 vs. 396.8 ± 165.8 s; P = 0.3). Rotational coronary angiography can be rapidly performed in any patient and provides a significant reduction in contrast and radiation utilization while at the same time providing adequate angiographic data to complement or replace standard coronary angiography in the evaluation of coronary artery disease. Catheter Cardiovasc Interv 2004;62:167–174.

Hypothyroidism and Primary Pulmonary Hypertension: An Autoimmune Pathogenetic Link?

Primary pulmonary hypertension (PPH) is an often fatal disease of unknown cause that primarily affects young women [1]. The relative roles of genetic predisposition, autoimmunity, viral infection, hormonal influences, and environmental and drug exposures are not known. Clinical associations may suggest common underlying etiologic mechanisms. We report four cases of PPH in female patients with low-titer positive antinuclear antibodies (ANA) and hypothyroidism, raising the possibility of an autoimmune pathogenetic link. Case Reports Patient 1 Exertional dyspnea developed in a 42-year-old Hispanic woman after a laparoscopic cholecystectomy in July 1991. In October 1991 chest radiography showed cardiomegaly and enlarged pulmonary arteries. Echocardiography, pulmonary function testing, a ventilation-perfusion lung scan, and a sleep study were consistent with PPH. Cardiac catheterization showed pulmonary arterial pressures of 80/48 mm Hg. The womans sister had mixed connective tissue disease. Medications included enalapril, warfarin, and supplemental oxygen. An ANA study was low-titer positive. Catheterization results from February 1992 are shown in Table 1. She entered the prostacyclin trial and was randomized to conventional therapy. In March 1992 she developed right-sided congestive heart failure with ascites and massive peripheral edema, jaundice, elevated liver function tests, a more prolonged prothrombin time, and depression. Results of hepatitis serologic tests were negative. Her thyroid-stimulating hormone (TSH) level was 11 mU/L (normal range, 0.5 to 5 mU/L). Low-dose thyroid supplementation (0.025 mg/d) was begun, and her TSH returned to normal in 1 to 2 weeks. Her clinical condition deteriorated and she died in April 1992. An autopsy showed plexiform lesions of the pulmonary arteries consistent with PPH, chronic hepatic congestion, and chronic thyroiditis with fibrosis and follicular atrophy. Table 1. Collagen Vascular Screen and Hemodynamic Data* Patient 2 A 45-year-old white woman had progressive fatigue and exertional dyspnea before 1988, when cardiac catheterization revealed a systolic pulmonary arterial pressure of 120 mm Hg. She had Raynaud phenomenon, a positive result of ANA, and carpal tunnel syndrome. Hypothyroidism had been diagnosed in 1965 and thyroid supplementation begun. Medications in March 1992 included nicardipine, furosemide, potassium supplementation, warfarin, thyroid supplementation, alprazolam, and albuterol and ipratropium bromide inhalers. She had an increased pulmonic closure sound, jugular venous distention, and pitting edema of the lower extremities. Chest radiography, ventilation-perfusion lung scan, echocardiography, and pulmonary function testing were consistent with PPH. A sleep study showed mild nonapneic desaturation. Result of an ANA was low-titer positive. Catheterization results from March 1992 are shown in Table 1. She entered the prostacyclin study, was randomized to prostacyclin plus conventional therapy, and is awaiting lung transplantation. Patient 3 A 33-year-old white woman became ill in 1988 during hospitalization for delivery of her second child. Postpartum cardiac catheterization revealed pulmonary hypertension. Result of an ANA was low-titer positive (Table 1). Her condition worsened, and in July 1991 thyroid tests revealed a TSH of 150 U/L (normal range, 0.5 to 5.0 U/L) and a T4 of 28.3 nmol/L (normal range, 63.1 to 157 nmol/L). Thyroid supplementation was begun at 0.05 mg daily and was increased to 0.088 mg daily. In December 1991 fluid retention, ascites, cyanosis, and worsening exertional dyspnea developed. In January 1992 she had hypotension, perioral and peripheral cyanosis, murmurs of tricuspid and pulmonic insufficiency, jugular venous distention, ascites, pitting edema of the lower extremities, and venous stasis changes. Chest radiography, pulmonary function testing, echocardiography, and a ventilation-perfusion lung scan were consistent with PPH. She was catheterized in January 1992 (see Table 1). She entered the prostacyclin study and was randomized to conventional therapy. Her condition improved with oxygen, warfarin, furosemide, and spironolactone treatment. Twelve weeks later she began prostacyclin [on a continuation study] in addition to her conventional therapy, and she had a single-lung transplantation in December 1992. Patient 4 A 53-year-old white woman noted exertional dyspnea and Raynaud phenomenon in autumn 1990 following nonspecific encephalitis. Echocardiography revealed severe pulmonary hypertension with right ventricular dysfunction. A ventilation-perfusion lung scan was read as being low probability for pulmonary emboli. Catheterization in December 1990 showed pulmonary arterial pressures of 50/25 mm Hg. Her medical history included spontaneous pneumothorax in 1958, reactive airway disease as a child, seasonal rhinitis, systemic hypertension during the past 2 years, and left lower lobe pneumonia in January 1991. Medications in March 1992 included diltiazem, lisinopril, hydrochlorothiazide, and guanfacine. She had mild systemic hypertension, an accentuated pulmonic heart sound, hepatojugular reflux, mild hepatomegaly, and pitting edema of the ankles. An ANA result was low-titer positive (see Table 1). Chest radiography, pulmonary function testing, echocardiography, and a ventilation-perfusion lung scan were consistent with PPH. She was catheterized in May 1992 (see Table 1). She entered the prostacyclin study and was randomized to receive prostacyclin plus conventional therapy. Thyroid tests in May 1992 (before prostacyclin) showed a TSH of 45 mU/L (normal range, 0.5 to 5.0 mU/L), T4 of 12.87 nmol/L (normal range, 51.5 to 154 nmol/L), and a T3 uptake of 0.38 (normal range, 0.25 to 0.35). Thyroid supplementation was begun. She is awaiting lung transplantation. Discussion We report four cases of hypothyroidism in female patients with severe PPH. Two had elevated TSH levels at our center and two were previously diagnosed and received thyroid supplementation elsewhere. All four patients were women with low-titer-positive ANAs and severe pulmonary hypertension in the absence of secondary causes. Two had Raynaud phenomenon. One woman was diagnosed with hypothyroidism before PPH was diagnosed. Except for a single case of chronic thyroiditis associated with pulmonary hypertension reported from Japan in 1968 [2], we believe this is the first report of a possible association between PPH and hypothyroidism. Thyroid dysfunction is frequently of autoimmune causes and is associated with other autoimmune diseases. Abnormal thyroid tests are common in patients with systemic lupus erythematosus [3]. Elevation of anti-DNA antibody titer has been reported during the thyrotoxic phase of silent thyroiditis [4] and in Grave disease [5]. Autoimmune thyroiditis occurs in scleroderma [6] and the Sjogren syndrome [7]. Pulmonary hypertension has been associated with autoimmune diseases including scleroderma, systemic lupus erythematosus, and mixed connective tissue disease [8-10]. Low-titer-positive ANAs occur in patients with PPH [1, 11]. Autoantibodies to Ku, a DNA-binding protein, which are found in some cases of systemic lupus erythematosus, scleroderma, myositis, and the Sjogren syndrome, have recently been reported in a subset of patients (23%) with PPH [12]. An autoimmune pathogenetic link between hyperthyroidism and PPH was proposed in the report of a single case [13]. Coexistence of hypothyroidism and PPH also raises the possibility of an underlying autoimmune process, which may be an important clue to the cause of PPH in this subgroup of patients. Raynaud phenomenon occurs in PPH [1] and in hypothyroidism, where it has been shown to improve with thyroid supplementation [14-16], suggesting a causal relationship [15]. Pulmonary artery vasospasm may precede chronic pulmonary hypertension and play an etiologic role [17]. Thus, thyroid hormone may play a vascular stabilizing role and thyroid insufficiency could contribute to vasospasm in Raynaud phenomenon and pulmonary hypertension. An association between PPH and hypothyroidism might be important for several reasons: It suggests an underlying autoimmune process contributing to both disorders; thyroid insufficiency could contribute to vasoconstriction; and monitoring of thyroid function may be indicated in PPH to avoid underdiagnosis of hypothyroidism. A prospective study is needed to validate our findings but may require considerable time to complete given the low prevalence of primary pulmonary hypertension.

Cardiac Dysfunction during Exercise in Uncomplicated Type 2 Diabetes

PURPOSE Type 2 diabetes mellitus (T2DM) has been associated with reduced peak exercise capacity (VO(2peak)). The causes of this impairment are not clearly established, but evidence suggests that abnormalities in cardiac function play a significant role. We hypothesized that exercise would be associated with impaired cardiac function and hemodynamics in recently diagnosed T2DM, even in the absence of clinically evident cardiovascular complications. METHODS After baseline normal echocardiography screening, 10 premenopausal women with uncomplicated T2DM (average duration of diagnosed T2DM, 3.6 yr) and 10 healthy nondiabetic women of similar age, weight, and activity levels performed a peak cardiopulmonary exercise test while instrumented with an indwelling pulmonary artery catheter for assessing cardiac function. On separate days, technetium-99m sestamibi (cardolite) imaging was performed to assess myocardial perfusion at rest and peak exercise in seven T2DM and seven control patients. RESULTS Resting measures of cardiac hemodynamics were similar in T2DM and control subjects. Absolute VO(2peak) (mL x min(-1)) and peak cardiac output (L x min(-1)) tended to be lower in T2DM than in control subjects but did not reach statistical significance. However, pulmonary capillary wedge pressure (PCWP) rose significantly more during exercise in T2DM than in controls (148% vs 109% increase at peak exercise, P < 0.01). Normalized myocardial perfusion index was lower in persons with diabetes than in controls (11.0 +/- 3.5 x e(-9) vs 17.5 +/- 8.1 x e(-9), respectively, P < 0.05) and inversely related to peak exercise PCWP (R = -0.56, P < 0.05). CONCLUSIONS Cardiac hemodynamics during graded exercise are altered in women with recently diagnosed T2DM as demonstrated by the disproportionate increase in PCWP at peak exercise compared with controls subjects. Cardiac abnormalities observed are potentially early signs of subclinical cardiac dysfunction associated with T2DM, which may precede the more greatly impaired cardiac function at rest and with exercise observed in longer established T2DM.

Three-Dimensional Analysis of in vivo Coronary Stent – Coronary Artery Interactions

Stent implantation results in important three-dimensional (3D) changes in arterial geometry which may be associated with adverse events. Previous attempts to quantify these 3D changes have been limited by two-dimensional techniques. Using a 3D reconstruction technique, vessel curvatures at end-diastole (ED) and end-systole (ES) were measured before and after stent placement of 100 stents (3 stent cell designs, 6 stent types). After stenting, the mean curvature at ED and ES decreased by 22 and 21%, respectively, and represents a straightening effect on the treated vessel. This effect was proportional to the amount of baseline curvature as high vessel curvature predicted more profound vessel straightening. When analyzed by stent cell design, closed-cell stents resulted in more vessel straightening than other designs (open cell or modified slotted tubes). Stent implantation resulted in the transmission of shape changes to stent ends and generated hinge points or buckling. Stent implantation creates 3D changes in arterial geometry which can be quantified using a 3D reconstruction technique.

Identification of risk factors for increased cost, charges and length of stay for cardiac patients

BACKGROUND In this study we explored different risk model options to provide clinicians with predictions for resource utilization. The hypotheses were that predictors of mortality are not predictive of resource consumption, and that there is a correlation between cost estimates derived using a cost-to-charge ratio or a product-line costing approach. METHODS From March 1992 to June 1995, 2,481 University of Colorado Hospital patients admitted for ischemic heart disease were classified by diagnosis-related group code as having undergone or experienced coronary bypass procedures (CBP), percutaneous cardiovascular procedures (PCVP), acute myocardial infarction (AMI), and other cardiac-related discharges (Other). For each diagnosis-related group, Cox proportional hazards models were developed to determine predictors of cost, charges, and length of stay. RESULTS The diagnosis groups differed in the clinical factors that predicted resource use. As the two costing methods were highly correlated, either approach may be used to assess relative resource consumption provided costs are reconciled to audited financial statements. CONCLUSIONS To develop valid prediction models for costs of care, the clinical risk factors that are traditionally used to predict risk-adjusted mortality may need to be expanded.